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CTRP3 attenuates post-infarct cardiac fibrosis by targeting Smad3 activation and inhibiting myofibroblast differentiation

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Abstract

C1q/tumor necrosis factor-related protein-3 (CTRP3) is a novel adipokine with modulation effects on metabolism, inflammation, and cardiovascular system. This study aimed to investigate the effect of CTRP3 on cardiac fibrosis and its underlying mechanism. The myocardial expression of CTRP3 was significantly decreased after myocardial infarction (MI). Adenovirus-delivered CTRP3 supplement attenuated myocardial hypertrophy, improved cardiac function, inhibited interstitial fibrosis, and decreased the number of myofibroblasts post-MI. In cultured adult rat cardiac fibroblasts (CFs), CTRP3 attenuated cell proliferation; migration; and the expression of connective tissue growth factor, collagen I, and collagen III induced by transforming growth factor (TGF)-β1. Moreover, CTRP3 inhibited whereas CTRP3 small interfering RNA (siRNA) facilitated the expression of α-SMA and profibrotic molecules induced by TGF-β1. CTRP3 also attenuated TGF-β1-induced Smad3 phosphorylation, nuclear translocation, and interaction with p300. CTRP3 increased the phosphorylation of AMP-activated protein kinase (AMPK) and Akt in both rat hearts and CFs. Adenine 9-β-d-arabinofuranoside (AraA), an AMPK inhibitor, abolished the protective effect of CTRP3 against TGF-β1-induced profibrotic response and Smad3 activation. Taken together, CTRP3 attenuates cardiac fibrosis by inhibiting myofibroblast differentiation and the subsequent extracellular matrix production. AMPK is required for the anti-fibrotic effect of CTRP3 through targeting Smad3 activation and inhibiting myofibroblast differentiation.

Key message

  • CTRP3 alleviates cardiac fibrosis in a rat post-MI model and in cardiac fibroblasts.

  • CTRP3 inhibits fibroblast-to-myofibroblast differentiation.

  • CTRP3 exerts anti-fibrotic effect through targeting Smad3 activation.

  • AMPK mediates the anti-fibrotic effect of CTRP3 by inhibition of Smad3 activation.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81270158 and 81470398), Research Fund for the Doctoral Program of Higher Education of China (20120001110009), and Beijing Natural Science Foundation (No. 7152083). We thank Dr. Sudhiranjan Gupta (Texas A&M Health Science Center, USA) for the valuable scientific advice.

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The authors have declared that no competing interest exists.

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    Authors and Affiliations

    1. Department of Physiology and Pathophysiology, Peking University Health Science Center, and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China

      Dan Wu, Hong Lei, Jin-Yu Wang, Cheng-Lin Zhang, Han Feng, Feng-Ying Fu, Li Li & Li-Ling Wu

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    1. Dan Wu
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    2. Hong Lei
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    Correspondence to Li Li or Li-Ling Wu.

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    Dan Wu and Hong Lei contributed equally to this work.

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    Wu, D., Lei, H., Wang, JY. et al. CTRP3 attenuates post-infarct cardiac fibrosis by targeting Smad3 activation and inhibiting myofibroblast differentiation. J Mol Med 93, 1311–1325 (2015). https://doi.org/10.1007/s00109-015-1309-8

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